Unsaturated oxacycles



United States Patent 3,374,245 UNSATURATED OXACYCLES Richard William James Carney, Murray Hill, and William Laszlo Bencze, New Providence, N.J., assiguors to Ciba Corporation, New York, N.Y., a corporation of Delaware No Drawing. Filed- Apr. 1, 1964, Ser. No. 356,664 9 Claims. (Cl. 260-4451) ABSTRAtIT OF THE DHSCLOSURE Compounds of the formula (CnHzn) P l i Re R: in which pH stands for an optionally substituted orthophenylene radical, one of the radicals R and R is a monocyclic carbocyclic aryl group containing a tertiary amino-lower alkoxy group and the other an aryl radical, n is an integer from 0' to 4, the group (C H separating the oxygen atom from the carbon atom of the double bond to which it is attached by at most 2 carbon atoms, their salts, their N-oxides, their salts of their N-oxides and their quaternary ammonium compounds. The compounds are useful as estrogenic, antifertility and antimicrobial agents.

SUMMARY OF THE INVENTION The present invention concerns basic ethers. More particularly, it relates to compounds having the formula f Ar; R

in which pH is a 1,2-phenylene radical, Ar is a monocyclic carbocyclic aryl group substituted by tertiary amino-lower alkyl-oxy, in which tertiary amino is separated from oxy by at least two carbon atoms, R is an aryl radical, and in the group of the formula (C H which separates the oxygen from the carbon atom of the double bond to which it is attached by at most two carbon atoms, the letter n is an integer from 0 to 4, salts, N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, as well as procedure for the preparation of such compounds.

The 1,2-phenylene (o-phenylene) radical is unsubstituted or may be substituted by one or more than one of the same or of different substituents attached to any of the four positions available for substitution. Substituents are primarily lower alkyl, e,g. methyl, ethyl, npropyl, isopropyl and the like, etherified hydroxyl, es pecially'lower alkoxy, e.g. methoxy,'ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, as well as lower alkenyloxy, e.g. allyloxy and the like, or lower alkylenedioxy, e.g. methylenedioxy and the like, or esterified hydroxyl, particularly halogeno (representing hydroxyl esterified by a hydrohalic acid), e.g. fiuoro, chloro, bromo and the like, as well as nitro, amino, or N-substituted amino, or N-substituted amino, such as N,N-di-lower alkyl-amino, e.g. N,N-dimethylamino, N,N-diethylamino and the like, trifluoromethyl, acyl, such as lower alkanoyl, e.g. acetyl, propionyl, pivalyl and the like, benzoyl, pyridoyl, e.g. nicotinoyl and the like, or any other suitable substituent. The 1,2-phenylene group Pb in the above "ice formula is primarily 1,2-phenylene, (lower alkyl)-l,2- phenylene, (etherified hydroxy)-l,2-phenylene, especially (lower alkoxy)-1,2-phenylene, as well as (lower alkenyloxy)-l,2-phenylene, (lower aJkylenedioxy-l,2- phenylene and the like, or (esterified hydroxy)-l,2- phenylene, particularly (halogeno)1,2-phenylene and the like, as well as (nitro)-l,2-phenylene, (amino)-l,2- phenylene, (N-substituted amino)-l,2-phenylene, such as (N,N-di-lower alkyl-amino)-1,2-phenylene and the like, (trifluoromethyl) 1,2 phenylene, (acyl) -1,2-phenylene, such as (lower alkanoyl)-l,2-phenylene, (benzoyl)-l,2- phenylene, (pyridoyl)-1,2-phenylene and the like, or any other suitably substituted 1,2-phenylene group.

A tertiary amino-lower alkyl-oxy-substituted monocyclic carbocyclic aryl group Ar has one or more than one tertiary amino-lower alkyl-oxy substituent, which may substitute any of the positions available for substitution; preferably a tertiary amino-lower alkyl-oxy group substitutes the 4-position. Such substituent is represented by the group of the formula O(C H -Am, in which the portion of the formula (C H stands for lower alkylene, having preferably from two to seven carbon atoms (i.e. the letter m is preferably an integer from two to seven, both inclusive), and separates the tertiary amino group Am from the oxygen atom by at least two carbon atoms. The group of the formula --(C H stands preferably for alkylene having from two to three carbon atoms (i.e. the letter In stands primarily for an integer from two to three) and separates the tertiary amino group Am from the oxygen atom by two to three carbon atoms. Such alkylene group is above all 1,2-ethylene, as well as lmethyl-l,2-ethylene, Z-methyl-LZ-ethylene or l,3-propylene, but may also be 1,3-butylene, 2,3-butylene, 3,4- butylene, 1,4-butylene, 1,4-pentylene, 1,5-pentylene, 1,5- hexylene, l,6hexylene, 1,7-heptylene and the like.

A tertiary amino group, such as the group Am in the above formula, is, for example, N,N-di-substituted amino, in which each of the srrbstituents, having preferably from one to ten carbon atoms, is, for example, an aliphatic radical, especially lower alkyl, e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary 'butyl, pentyl, neopentyl and the like, as Well as lower alkenyl, e.g. allyl, methylallyl and the like a cycloaliphtic radical, such as cycloallyl having from three to seven, preferably five or six, ring carbon atoms, e.g. cyclopentyl, cyclohexyl and the like, a cycloaliphtic-aliphatic radical, such as cycloalkyl-lower alkyl, in which cycloalkyl has from three to seven, preferably five or six, ring carbon atoms, e.g. cyclopentylmethyl, 2-cyclohexylethyl and the like, a carbocyclic aryl radical, such as monocyclic carbocyclic aryl, e.g. phenyl and the like, a carbocyclic aryl-aliphatic radical, such as monocyclic carbocyclie aryl-lower alkyl, for example, phenyl-lower alkyl, e.g.benzyl, l-phenylethyl, 2-phenylethyl and the like, or any other equivalent radical. The above substituents, particularly lower alkyl, may

also carry functional groups, such as hydroxyl, lower phenyl-lower alkyl-amino, e.g. N-benzyl-N-methyl-amino,

N-benzyl N ethyl amino, N-ethyl-N-( 1-phenylethyl)- amino, N-methyl-N-(2-phenylethyl)-amino and the like, or any other equivalent N,N-di-substituted amino group. N,N-di-substituted-amino groups, in which the substituents carry functional groups are, for example, N-hydroxy lower alkyl-N-lower alkyl-amino, in which hydroxyl is separated from the amino-nitrogen by at least two, preferably by two to three, carbon atoms, e.g. N-(2- hydroxyethyl)-N-methyl-amino and the like, N,N-di-hydroxy-lower alkyl-amino, in which hydroxyl is separated from the amino-nitrogen by at least two, preferably by two to three, carbon atoms, e.g. N,N-di-(2-hydroxyethyl)- amino and the like.

The tertiary amino group, such as the group Am in the above formula, may also represent an N,N-disubs.itutcd amino group, in which the two substituents are taken together and form a divalent radical, such as a l-N,N-alkylene-imino group, in which alkylene has from four to eight carbon atoms, such as a l-pyrrolidino group, e.g. l-pyrrolidino, 2-methyl-l-pyrrolidino and the like, a l-piperidino group, e.g. l-piperidino, Z-methyl-l-piperidino, 4- methyl-l-piperidino, 3-hydroxy-1-piperidino, 3-acetoxy-lpiperidino, 3-hydroxymethyl-l-piperidino and the like, 1- N,N-(1,6-hexylene)-imino, l-N,N-( 1,7-heptylene -imino and the like, a l-N,N-aza-alkylene-imino group, in which alkylene has from four to six carbon atoms, and the two nitrogen atoms are separated by at least two carbon atoms, particularly a l-N,N-(N-lower alkyl-aza-alkylene)-imino group, in which alkylene has from four to six carbon atoms, and the two nitrogen atoms are separated by at least two carbon atoms, such as l-piperazino or, particularly, 4-lower alkyl-l-piperazino, e.g. 4-methyl-l-piperazino, 4-ethyl-l-piperazino and the like, as well as 4-hydroxyethyl-l-piperazino, 4-acetoxyethyl-l-piperazino and the like, a 1-N,N-(3-aza-1,6-hexylene)-imino group, particularly a 1-N,N-(3-aza 3 lower alkyl-l,6-hexylene)- imino group, e.g. 1-N,N-(3-aza-3-methyl-1,6-hexylene)- imino and the like, or a 1-N,N-(4-aza-l,7-heptylene)- imino group, particularly a l-N,N-(4-aza-4-lower alkyl- 1,7-heptylene)-imino group, e.g. l-N,N-(4-aza-4-methyl- 1,7-heptylene)-imino and the like, or a 1-N,N-0xa-alkylene group, in which alkylene has preferably four carbon atoms, and the oxygen atom is separated from the nitrogen atom by two carbon atoms, such as a 4-morpholino group, e.g. 4-morpholino, 3-methyl-4-morpholino and the like, or a l-N,N-thiaalkylene-imino group, in which alkylene has preferably four carbon atoms, and the sulfur atom is separated from the nitrogen by two carbon atoms, such as a 4-tiamorpholino group, e.g. 4-thiamorpholino and the like, or any other equivalent N,N-disubstituted amino group.

In the tertiary amino-lower alkyl-oxy group, the lower alkyl portion, either partially or in toto, may form part of a saturated heterocyclic ring system, the tertiary amino group Am being a ring member and being separated from the oxy group by at least two carbon atoms. Such tertiary amino-lower alkyl groups are, for example, l-methyl- Z-piperidinomethyl, 1-methyl-3-piperidinomethyl, l-ethyl- 4-piperidino, 1-methyl-3-pyrrolidinomethyl and the like.

Apart from being substituted by tertiary amino-lower alkyl-oxy, the monocyclic carbocyclic aryl group Ar may have one or more than one additional substituent, which may be attached to any of the positions available for substitution. Such substituents are lower alkyl, halogeno, trifluoromethyl, or any other suitable substituent, such as one of those substituting the 1,2-phenylene group Ph. As mentioned above, the tertiary amino-lower alkyl-oxysubstituted group Ar may have more than one tertiary amino-lower alkyl-oxy group of the formula in which Am and the group of the formula --(C,,,H have the previously-given meaning.

The aryl group R is a carbocyclic aryl radical, particularly monocyclic carbocyclic aryl, e.g. phenyl or substituted phenyl, in which one or more than one of the same or of different substituents are attached to the phenyl group. These substituents are represented, for example, by those substituting the 1,2-phenylene radical, or by tertiary amino-lower alkyl-oxy, and may be attached to any of the positions available for substitution. Substituted phenyl groups representing R are primarily (lower alkyl)- phenyl, (etherified hydroxy)-phenyl, especially (lower alkoxy)-phenyl, as well as (lower alkenyloxy)-phenyl, (lower alkylenedioxy)-phenyl and the like, or (esterified hydroxy)-phenyl, especially (halogeno)-phenyl and the like, as well as (nitro)-phenyl, (amino)-phenyl, (N-substituted amino)-phenyl, such as (N,N-di-lower alkylamino)-phenyl and the like, (trifluoromethyl)-phenyl, (acyl)-phenyl, such as (lower alkanoyl)-phenyl, (benzoyl)-phenyl, (pyridoyl)-phenyl and the like, as well as [Am(C H )-O]-phenyl, in which Am and the group -(C H have the previously-given meaning. The aryl radical representing R may also be a heterocyclic aryl group, particularly monocyclic heterocyclic aryl, such as pyridyl, e.g. 3-pyridyl, 4-pyridyl and the like.

The group of the formula --(C,,H in which the letter n is an integer from 0 to 4, is either a direct bond between the oxygen and the carbon atom of the double bond to which it is attached, or a lower alkylene radical separating the oxygen from that carbon atom by at most two carbon atoms. Such lower alkylene radical is above all methylene, as well as 1, 2-ethylene, but may also be 1,1-ethylene, l-methyl-l, 2-ethylene, 1,1-propylene, 1,1- butylene, l,l-isobutylene and the like. The compounds of this invention have, therefore, the benzofuran (or benzo[b]furan or coumarone) ring system, the 2H- chromene (or 2H-l-benzopyran) ring system, or the 2,3- dihydro-l-benzoxepin ring system.

Salts of the compounds of this invention are acid addition salts, such as pharmaceutically acceptable acid addition salts with inorganic acids, e,g, hydrochloric, hydrobromic, sulfuric, phosphoric acids and the like, or organic acids, such as organic carboxylic acids, e.g. acetic, propionic, pivalic, glycolic, lactic, malonic, succinic, maleic, hydroxy-maleic, malic, tartaric, citric, benzoic, salicylic, Z-acetoxybenzoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, e.g. methane sulfonic, ethane sulfonic, ethane 1,2-disulfonic, 2-hydroxyethane sulfonic, p-toluene sulfonic, naphthalene ,2-sulfonic acid and the like. Other addition salts with acids may be useful as intermediates, for example, in the preparation of pharmaceutically acceptable acid addition salts or in the purification of the free compounds, as well as for identification or characterization purposes. Salts, which are prepared primarily for the latter, are, for example, those with certain inorganic acids, e.g. perchloric acid and the like, with acidic organic nitro compounds, e.g. picric, plcrolonic, fiavianic acid and the like, or with metal complex acid, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like. Monoor poly-salts may be formed depending on the number of salt-forming groups and/or the conditions used for the salt formation.

Also included within the scope of the present invention the N-oxides of the aforementioned compounds, as well as the acid addition salts of such N-oxides, for example, the pharmaceutically acceptable, non-toxic acid addition salts of N-oxides, such as those with the above-mentioned acids.

Quaternary ammonium derivatives of the compounds of this invention are those formed with reactive esters of alcohols and strong inorganic or organic acids, particularly those with lower aliphatic halides, sulfates, or organic sulfonates, such as lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide, iodide-and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, lower alkyl lower alkane sulfonates, e.g. ethyl or methyl methane sulfonate, ethane sulfonate and the like, lower alkyl lower hydroxy-alkane sulfonates, e.g. methyl 2-hydroxy-ethane sulfonate and the like, or lower alkyl monocyclic carbocyclic aryl sulfonates, e.g. methyl p-toluene sulfonate, ethyl p-toluene sulfonate and the like, as well as those with carbocyclic aryl-aliphatic halides, such as phenyl-lower alkyl halides,

e.g. benzyl, l-phenylethyl or Z-phenylethyl chloride, bromide or iodide and the like. Also included as quaternary ammonium compounds are the corresponding quaternary ammonium hydroxides, and the quaternary ammonium salts with acids other than hydrohalic, sulfuric or organic sulfonic acids, particularly those with the organic carboxylic acids mentioned hereinabove.

The compounds of this invention have estrogenic properties, and are, therefore, useful in lieu of other estrogenic agents, e.g. estradiol, stilbestrol, hexestrol and the like, for example, in the treatment of animals to increase weight gain, efiiciency of feed utilization and the like.

Furthermore, it has also been found that, when given to female rats, the compounds of this invention inhibit pregnancy; They are, therefore, useful as antifertility agents to prevent pregnancy.

In addition, compounds of this invention have antimicrobial eifects, such as antifungal properties, for example, against fungi causing superficial dermatophytoses, such as Trichophyton mentagrophytes, Trichophyton gallinae, Triclwphyton interdigitale, Microsporum audouini, Microsporum canis, Microsporum gypseum and the like, against fungi causing chronic infections of the skin and the subcutaneous tissue, such as Sporotrichium schenkii and the like, or fungi causing deep-seated systemic mycoses (yeasts), such as Candida albicans, Cryptococcus neoformans, Histoplasmu capsulatum and the like, effects against actinomyces, such as Nocardia asteroides and the like, against bacteria, such as gram-positive bacteria, for example, Diplococcus pneumoniae, Staphylococcus aureus and the like, or gram-negative bacteria, for example, Escherichia coli, Pseudomonas aeruginosa and the like, and against protozoa, such as Trichomonas vaginalis and the like. Such compounds are, therefore, useful in the treatment of microbial infection caused, for example, by such fungi, actinomyces, bacteria and protozoa of the above type.

(lompounds of this invention, especially those with more than one tertiary amino-lower alkoxy group substituting Ar, have taeniacidal (anti-tapeworm) properties, and are, therefore, useful as taeniacides in the treatment of tapeworm infections, caused, for example, by Hymenolepas nana, Dypilidium canium, Taenia pisiformis and the like.

Particularly useful are the compounds having the following formula:

Ra Rb in which Ph' stands primarily for 1,2-phenylene, (lower alkyl)-1,2-phenylene, (lower alkoxy)-l,2-phenylene, or (halogeno)-1,2-phenylene, R is phenyl, (lower alkyl)- phenyl, (lower alkoxy)-phenyl or (halogeno)-phenyl, the letter n stands for one of the integers from 0 to 2, particularly for 1, Am stands for N,N-di-lower alkylamino, N,N-alkylenesimino, in which alkylene has preferably from four to seven carbon atoms, 4-morpholino or 4- lower alkyl-l-piperazino, the group of the formula -(C -H stands for alkylene having from two or to three, preferably two, carbon atoms, (i.e. the letter In" stands for one of the integers 2 and 3, preferably for the integer 2), and separates the group Am from the oxygen atom by two or three, preferably by two, carbon atoms, and each of the groups R and R is hydrogen, halogeno, especially chloro, or the group of the formula in which Am and the group of the formula have the previously-given meaning, and the acid addition salts, particularly the pharmaceutically acceptable acid addition salts, thereof. In the above compounds, the group of the formula O(C H ')Am preferably substitutes the 4-position of the phenyl port-ion.

The above group of compounds represented by those of the following formula:

in which Am is N,N-di-1ower alkyl-amino or N,N-alkylene-imino, in which alkylene has from four to seven carbon atoms, each of the groups R, and R is hydrogen or the group of the formula -OCI-I CH Am, in which Am has the previously-given meaning, and each of the groups R R and R is hydrogen, lower alkyl, lower alkoxy or halogeno, or acid addition salts, particularly pharmaceutically acceptable acid addition salts thereof.

The compounds of this invention are useful in the form of composition suitable for enteral, e.g. oral, parenterial or topical use; essentially, they comprise a pharmacologically effective amount of one of the new compounds of this invention in admixture with a pharmaceutically acceptable, organic or inorganic, solid or liquid carrier, which usually represents the major portion by weight of such compositions. These preparations are in solid form, for example, as capsules, tablets, dragees and the like, in liquid form, for example, as solutions, suspensions and the like, or in the form of emulsions, e.g. salves, creams and the like. Suitable carrier materials, are, for example, starches, e.g. corn starch, wheat starch, rice starch and the like, sugars, e.g. lactose, glucose, sucrose and the like, stearic acid or salts thereof, e.g. magnesium stearate, calcium stearate and the like, stearyl alcohol, talc, gums, acacia, tragacanth, polyalkylene glycols, propylene glycol and the like. The quantity and the nature of the carrier ingredients can vary widely and depend, inter alia, upon the desired physical appearance or size of the composition, method of manufacture and the like. Encaspulation may be effected by using, if desired, the same excipients as those for tablets. If necessary, the compositions may contain other auxiliary substances, such as preserving, stabilizing, wetting, emulsifying agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other pharmacologically useful substances. The compounding of the formulations is generally carried out in the manner normally employed in the art, i.e. by'manufacturing a mixture, 2. granulate and the like. Any compatible color, approved and certified under the provisions of the Federal Food, Drug and Cosmetic Law may be used for aesthetic purposes or as a means of identification.

The compounds of the present invention are prepared according to methods known per se; for example, they are formed by converting in a compound of the formula:

Ar R in which Ph, R and the letter n have the previously-given meaning, and Ar, is a monocyclic carbocyclic aryl group substituted by R capable of being converted into tertiary amino-lower alkyl-oxy, in which tertiary amino is separated from the oxygen by at least two carbon atoms, or a salt thereof, the monocyclic carbocyclic aryl group Ara substituted by R into the monocyclic carbocyclic aryl group Ar substituted by tertiary amino-lower alkyl-oxy, and, if desired, converting a resulting salt into the free compound or into another salt, and/or, if desired, converting a resulting compound into an N-oxide or a quaternary ammonium compound thereof, and/or, if desired, converting a resulting compound or an N-oxide into a salt thereof, and/or, if desired, converting a quaternary ammonium compound into another quaternary ammonium compound, and/or, if desired, separating a mixture of isomers into the single isomers.

In the starting material, the group Ar may have one or more than one group R which is converted into tertiary amino-lower alkyl-oxy in one step or in stages. A particularly suitable group R is hydroxyl; its conversion into tertiary amino-lower alkyl-oxy is carried out according to known procedures. Usually, the starting material, in which Ara is substituted by hydroxyl representing R0, or preferably a salt thereof, is reacted with a reactive ester of a teriary amino-lower alkanol, in which the tertiary amino group is separated from hydroxyl by at least two carbon atoms, particularly a compound of the formula Am(C H )X, in which Am and the group of the formula (C H have the previously-given meaning, and X stands for a reactive esterified hydroxyl group. The latter is above all a hydroxyl group esterified with a strong mineral acid, such as a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like; the group X represents primarily halogeno, e.g. chloro, bromo, and the like. It may also be a hydroxyl group esterified with a strong organic sulfonic acid, such as a lower alkane sulfonic acid, e.g. methane sulfonic, ethane sulfonic acid and the like, or a monocyclic carbocyclic aryl-sulfonic acid, e.g. p-toluene sulfonic acid and the like; the group X may, therefore, also stand for lower alkyl-sulfonyloxy, e.g. methylsulfonyloxy, ethylsulfonyloxy and the like, or monocyclic carbocyclic aryl-sulfonyloxy, e.g. p-tolylsulfonyloxy and the like. The preferred reactive esters of a tertiary amino-lower alkanol are those having the formula in which Am and the group of the formula (C H have the previously-given meaning, and Hal represents halogeno, particularly chloro.

As noted above, the starting material is preferably used in the form of a salt thereof. Such salt, for example, a metal salt, particularly an alkali metal salt, e.g. lithium, sodium, potassium and the like, salt, as well as an alkaline earth metal salt, or any other suitable salt, is formed, for example, by treatment of the starting material with a metal salt-forming reagent, such as an alkali metal hydride or an alkali metal amide, e.g. lithium hydride, sodium hydride, sodium amide, potassium amide and the like, or any other suitable reagent, such as an alkali metal lower alkoxide or alkaline earth metal lower alkoxide, e.g. lithium, sodium, potassium or barium methoxide, ethoxide or tertiary butoxide and the like, an alkali metal compound of a hydrocarbon, e.g. butyl lithium, phenyl lithium, phenyl sodium and the like. The preparation of the salt is usually carried out in the presence of an inert solvent, e.g. hexane, benzene, toluene, xylene, diethyl, ether, p-dioxane, tetrahydrofuran, diethyleneglycol dimethyl ether, N,N-dimethylformamide and the like, or any other suitable solvent, such as a lower alkanol, e.g. methanol, ethanol and the like, or solvent mixture, if necessary, while cooling or at an elevated temperature, and/or in the atmosphere of an inert gas.

The reaction of the starting material, particularly a metal compound thereof, with the reactive ester of a tertiary amino-lower alkanol is carried out in the presence of a suitable diluent, for example, in the solvent or solvent mixture used for the preparation of a metal compound, if necessary, while cooling or at an elevated temperature, and/or, in the atmosphere of an inert gas, e.g. nitrogen. Formation of the metal compound of the starting material may also be achieved in situ; for example, the free starting material and the reactive ester of the tertiary aminolower alkanol may be reacted in the presence of a saltforrning reagent.

Conversion of hydroxyl representing R into tertiary amino-lower alkyl-oxy may also be achieved by treating the starting material, in which Ar is a monocyclic carbocyclic aryl radical substituted by hydroxyl representing R with a tertiary aminolower alkanol, in which the tertiary amino group is separated from the hydroxyl group by at least two carbon atoms, in the presence of a di-substituted carbonate. The latter is, for example, a di-aryl carbonate, e.g. diphenyl carbonate and the like, or, more particularly, a di-lower alkyl carbonate, e.g. dimethyl carbonate, ethyl methyl carbonate, diethyl carbonate, dibutyl carbonate and the like. The reaction is carried out at an elevated temperature, for example, between about and about 210, preferably between about 180 and about 200, and, if desired, in the presence of a transesterification catalyst enhancing the rate of the reaction, e.g. sodium, potassium, sodium carbonate, potassium carbonate, sodium aluminate and the like, a metal lower alkoxide, e.g. sodium ethoxide, titanium butoxide and the like, or any other analogous reagent. The reaction is usually performed in the absence of an additional solvent, an excess of the di-substitu-ted carbonate serving as the diluent, but may also be carried out in the presence of a further solvent or solvent mixture, if necessary, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.

Another group R capable of being converted into tertiary amino-lower aikoxy is the group of the formula OC(:O)-Y, in which Y represents halogeno or etherified hydroxyl. The group Y is particularly lower alkoxy, e.g. methoxy, ethoxy, n-butyloxy and the like, as well as phenyloxy or any other analogous etherified hydroxyl group, whereas halogeno, representing Y, is particularly chloro, as well as bromo and the like. Upon reacting a starting material having a group Ar substituted by the above group representing R with a tertiary aminolower alkanol, in which tertiary amino is separated from the hydroxyl group by at least two carbon atoms, the desired compound can be formed. The reaction is carried out under the previously-described conditions, i.e. at an elevated temperature, preferably at between 180 and 200, and, if desired, in the presence of a transesterification reagent, such as one of those previously-described; the reaction is preferably performed in the absence of a diluent, but may also be carried out in the presence of a solvent or solvent mixture, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.

A further group R capable of being converted into tertiary amino-lower alkoxy is also a reactive esterified hydroxy-lower alkyl-oxy group. The latter is particularly a group of the formula --O(C,-,,H )-X, in which X and the group of the formula --(C,,,'H have the previously-given meaning. The reactive esterified hydroxyl group X is primarily a group Hal representing halogeno, particularly chloro; it may also be a suitable organic sulfonyloxy group, such as one of those mentioned above.

A starting material having a group Ar substituted by reactive esterified hydroxy-lower alkyl-oxy representing R is reacted with a secondary amine, having preferably the formula H-Am, in which Am has the above-given meaning, to yield the desired compound. The reaction is preferably carried out in such manner, that an excess of the amine or of any other suitable acid-neutralizing agent, e.g. potassium carbonate and the like, is present to neutralize the generated acid. If desired, the reaction mixture is diluted with a suitable inert solvent or solvent mixture; if necessary, the reaction is carried out while cooling or at an elevated temperature, and/ or in the atmosphere of an inert gas, e.g. nitrogen, and/or in a closed vessel.

The starting materials used in the above reaction are necessary, converting a resulting compound of the formula 9. prepared according to known methods. Thus, starting materials, in which Ar is substituted by hydroxyl representing R such as those represented by the formula in which Ph', R and the letter n have the previously given meaning, and each of the groups R and R is hydrogen, halogeno or hydroxyl, above all the compounds of the formula:

l R o! in which R R, and R have the previously given meaning, and each of the groups R, and R is hydrogen or hydroxyl, may be prepared, for example, by reacting a compound having the formula:

l-phenylethyloxy and the like), and M is the cation of certain metals of the I-A group of the Periodic System (i.e. of certain alkali metals), e.g. lithium, sodium and the like, or the group of the formula Hal-Mg in which Hal is halogeno, e.g. chloro, bromo, iodo and the like, if

in which Ph, Ar R and the letter n have the previously given meaning, into the unsaturated compound of the formula in which Ph, Ar R and the letter it have the previously given meaning, and converting in the latter the group Ar substituted by R,,' into the group Ar substituted by R Y The reaction'of the ketone intermediate with the organometallic reagent is carried out according to known methods. Usually, the reaction is carried out in the presence of a solvent-or solvent mixture, if necessary, while cooling or at an elevated temperature, and/or in the atmosphere of an inert gas, eg. nitrogen. Furthermore, 7

the Method of Entrainment, described by Kharash and Reinmuth, Grignard Reactions of Nonmetallic Substances (Prentice Hall, 1954), or a cyclic reactor, as described by Lawesson, Acta Chim, Scand., vol. 12, p. 1 (1958), may have to be employed to bring about the formation of the Grignard reagent or the reaction of the latter with the ketone intermediate.

If necessary, the product resulting from the reaction of the ketone intermediate with the organo-metallic reagent may have to be converted into the unsaturated intermediate. This may be achieved, for example, by dehydration, if required, at an elevated temperature, and/ or in the presence of an acidic reagent, such as an acid, e.g. hydrochloric, hydrobromic, sulfuric, acetic, p-toluene sulfonic acid and the like, as well as any other suitable acidic reagent, e.g. thionyl chloride, phosphorus pentachloride, ammonium chloride, acetyl chloride, p-toluene sulfonyl chloride, acetic anhydride, pyridine hydrochloride and the like, or a mixture thereof, which reagents may also be used in the presence of a solvent or solvent mixture. The formation of the unsaturated compound may also be accomplished, for example, by converting the hydroxyl group of the intermediate product into a reactive esterified hydroxyl group by esterification, for example, into an acyloxy group or into halogeno, according to known methods, and then eliminating the elements of an acid, if necessary, at an elevated temperature, and/ or, in the presence of a suitable base.

In a resulting compound, R substituting Ar is converted into hydroxyl, for example, by acid hydrolysis with an aqueous hydrohalic acid, e.g. hydrobromic acid and the like, by hydrogenolysis with hydrogen in the presence of a suitable catalyst, eg. a palladium catalyst, or any other appropriate procedure.

Furthermore, in a starting material, in which Ar is substituted by hydroxyl, the latter may be converted into the group --OC(=O)Y, in which Y has the previously-given meaning, for example, according to any method suitable for the esterification of a phenolic hydroxyl group, such as formation of an alkali metal compound of the phenolic intermediate and reaction of the latter with an ester of the acid of the formula or the halide thereof.

In addition, R substituting Ar in a resulting starting material, whenever representing hydroxyl, may be converted into a reactive esterified hydroxy-lower alkyl-oxy group by treating the starting material having such free hydroxyl group or a salt thereof with a lower alkyleneoxide, a halogeno-lower' alkanol, in which halogeno is separated from hydroxyl by at least two carbon atoms, or

with a lower alkylene halide, in which the two halogeno atoms are separated by at least two carbon atoms, for example, a chloro-lower alkyl bromide, in which chloro is separated from bromo by at least two carbon atoms, and, if necessary, converting in a resulting compound, in which Ar is substituted by hydroxy-lower alkyl-oxy, hydroxyl into esterified hydroxyl according to known methods, for example, by treatment with a thionyl halide, e.g. thionyl chloride and the like, a phosphorus halide, e.g. phosphorus tribromide and the like, or with an organic sulfonic acid halide, e.g. chloride and the like, or any other suitable method.

The compounds of this invention are also prepared by reacting a compound of the formula 11 and Ar is the anion of a compound of the formula ArH, in which Ar has the previously-given meaning, and, if necessary, converting a resulting intermediate of the formula n Zn) P t (I) J oj a onnmr in which Ph, Ar, R and the letter 11 have the previously given meaning, into the desired unsaturated compound, and, if desired, carrying out the optional steps.

The above reaction is carried out according to known methods, preferably in the presence of a diluent. The cation M is more especially the cation of the formula MgHal, in which Hal is halogeno, especially bromo. A Grignard reagent representing HalMg Ar is prepare-d, for example, by reacting a compound of the formula Hal-Ar, in which Ar and Hal have the previouslygiven meaning, the latter being above all bromo, with magnesium in the presence of a suitable diluent, e.g. tetrahydrofuran and the like, if necessary, by initiating the reaction with a suitable reagent, e.g. methyl iodide and the like. It is then treated with the starting material, if desired, after having replaced or diluted the solvent with another diluent, e.g. toluene, anisole and the like. The reaction is carried out while cooling or preferably at an elevated temperature, if necessary, in the atmosphere of an inert gas, e.g. nitrogen.

If necessary, a resulting hydroxyl intermediate has to be converted into the desired unsaturated compound according to the previously described procedure, for example, by dehydration, conversion of the hydroxyl group into an esterifie-d hydroxyl group and elimination of the elements of an acid, or any other appropriate procedure.

The starting materials used in the above procedure are known or may be prepared according to known methods.

The compounds of this invention are also prepared, for example, by reacting a compound of the formula in which Ph, Ar, R and the letter n have the previously given meaning, into the desired unsaturated compound, and, if desired, carrying out the optional steps.

The above reaction is carried out as previously described. The starting material is prepared, for example, by converting in a compound of the formula in which Ph, Ar and the letter n have the previously given meaning, the monocyclic carbocyclic aryl group An, substituted by R capable of being converted into hydroxyl, eg. lower alkoxy and the like, into the monocyclic carbocyclic aryl group Ar substituted by hydroxyl, and converting in the resulting compound the monocyclic carbocyclic aryl group Ar substituted by hydroxyl into tertiary amino-lower alkyl-oxy substituted monocyclic carbocyclic aryl group Ar; these reactions are carried out according to the methods previously described.

The compounds of this invention may also be prepared, for example, by eliminating the elements of hydrohalic acid of the formula H-Hal from a compound of the formula in which Ph, Ar, R and the letter n have the previously given meaning, and Hal stands for halogeno, especially chloro or bromo, and, if desired, carrying out the optional steps.

The elimination of hydrohalic acid from the starting material is carried out according to known methods, usually by treatment with a base, such as an alkali metal hydroxide, e.g. sodium hydroxide, potassium hydroxide and the like, or an organic base, e.g. pyridine, collidine, quinoline and the like. The reaction is usually performed in the presence of a diluent, such as a lower alkanol, or a mixture thereof, whereby a liquid organic base may simultaneously serve as a solvent, if necessary, at an elevated temperature, and/or, in the atmosphere of an inert gas, e.g. nitrogen.

The starting material used in the above procedure is prepared according to known methods, preferably by reacting a compound of the formula in which Ph, Ar, R and the letter 11 have the previously given meaning, and which is prepared according to the procedure described in our application Serial No. 356,- 667, filed April 1, 1964, now US. Patent No. 3,340,276, with a suitable halogenating reagent, particularly an N- halogeno-dicarboxylic acid imide, e.g. N-chloro-succinimide, N-bromo-succinimide, N-chloro-hydanton and the like, in the presence of a suitable diluent, e,g. chloroform, methylene chloride, benzene and the like, if necessary, at an elevated temperature, or any other suitable procedure.

A resulting salt is converted into the free base, for example, by treating it with an alkaline regent, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, a metal carbonate, e.g. sodium, potassium or calcium carbonate or hydrogen carbonate and the like, ammonia and the like, or by treatment with a suitable hydroxyl ion exchange resin.

A resulting salt, particularly a salt with an inorganic acid, can be converted into another salt according to known methods, for example, by reacting it with a suitable metal, e.g. sodium barium, silver and the like, salt of an acid, preferably in the presence of a diluent, in which a resulting inorganic salt is insoluble and is thus removed from the reaction. A salt may also be converted into another salt by treating it with an anion exchange preparation.

A free base is converted into an acid addition salt thereof according to known methods, for example, by reacting it or a solution thereof in a suitable solvent or solvent mixture with the acid or a solution thereof, or with a suitable anion exchange prepartion, and isolating the desired salt. A salt may be obtained in the form of 13 a hydrate thereof or may include solvent of crystallization. 1

An N-oxide of the compounds of this invention is prepared according to known methods, for example, by treating the free base with a suitable N-oxidizing reagent, such as hydrogen peroxide, ozone or a peracid, e.g. peracetic, perbenzic, monoperphthalic, persulfuric acid and the like, in the presence of a suitable inert diluent. An N-oxide is converted into an acid addition salt thereof according to the above procedure.

Quaternary ammonium derivatives of the compounds of this invention are obtained according to known methods, for example, by reacting the base with the reactive ester of an alcohol and a strong acid, such as, for example, with one of the lower alkyl halides, di-lower alkyl sulfates, lower alkyl organic sulfonates or phenyl-lower alkyl halides described above. The quaternizing reaction is performed in the absence or presence of a solvent, while cooling or at an elevated temperature, if necessary, in a closed vessel and/or in the atmosphere of an inert gas, e.g. nitrogen and the like.

Resulting quaternary ammonium compounds may be converted into other quaternary ammonium compounds, such as the quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with a hydroxyl ion exchange preparation or any other suitable method. A quaternary ammonium hydroxide is converted into a quaternary ammonium salt by reacting theformer with a suitable acid. A quaternary ammonium salt is also converted directly into another quaternary ammonium salt; for example, a quaternary ammonium iodide, when reacted with freshly prepared silver chloride or with hydrochloric acid in anhydrous a'mmonium 'compound may be obtained in the form of a hydrate thereof or may contain solvent of crystallization. A mixture of resulting isomeric compounds may be separated into the single isomers. For example, a mixture of diastereoisomers is separated into the individual racemic compounds on the basis of physico-chemical differences, such as solubility, for example, by fractional crystallization, as well as by fractional distillation and the like. Racemates are resolved into the optically active dand l-forms according to known resolution procedures, for example, by forming a salt of the free racemic base with one of the optically active forms of an acid containing an asymmetric carbon atom. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tartaric (l-tartaric) and L-tartaric (d-tartaric) acid, as well as the optically active forms of malic, mandelic, camphor sulfonic, quinic acid and the like. A resulting mixture of salts of the optically'active acid with the antipodes of the-base racemate isseparated into the single salts on the basis of physico-chemical differences, for example, by fractional crystallization. From a resulting salt, the free and optically active base is obtained according to the method described above, and a free and optically active base can be converted into its acid addition salt, N-oxide, salt of an N-oxide or quaternary ammonium compound according to the procedures described above.

The invention also comprises any modification of the process wherein a compoundformed as an intermediate at any stage of the process, is used as starting material and the remaining step(s) of the process is(are) carried out, as well as anynew intermediates.

In the process'of this invention such starting materials arepreferably used which lead to final products mentioned in the beginning as preferred embodiments of the invention.

l 4 The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperature are given in degrees Centigrade.

Example 1 To 0.49 g. of magnesium (dried :by heating under a stream of gaseous nitrogen) is added 4 ml. of tetrahydrofuran and 4 drops of methyl iodide, to initiate the reaction, and then a solution of 5.44 g. of 4-(2-N,N-diethyaminoethyl)-oxy-bromobenzene in 60 ml. of tetrahydrofuran. The reaction mixture is refluxed. until the magnesium has disappeared and is then treated with 5.1 g. of 7.-methoxy-3-phenyl-chroman-4-one in 60 ml. of tetrahydrofuran. Refluxing is continued for four hours, and after standing overnight, the reaction mixture is diluted with water; the resulting gel is separated, washed with diethyl ether, and the resulting organic solutions are combined and concentrated under reduced pressure. The remaining oil is dissolved in diethyl ether and extracted with 5 percent hydrochloric acid. A yellowish-brown oil separates, which crystallizes from a mixture of acetone and diethyl ether to yield 5.25 g. of the 4-[4-(2-N,N- diethylaminoethyl)-oxy-phenyl]-7-methoxy 3 phenyl- ZH-chromene hydrochloride of the formula which melts at 123-125 and analyzes as follows:

Calcd. for C H NO -HCI: N, 3.01. Found: N, 2.83. The starting material used in the above procedure is prepared as follows: A solution of 90.0 g. of 3-methoxy phenol in 100 ml. of water containing 20.0 g. of sodium hydroxide is added to 100.0 g. of ot-bromo-acetophenone in 120 ml. of acetone. After heating on the steam bath for fifteen minutes, the acetone is removed under reduced pressure; and-the resulting aqueous solution is'poured onto ice while stirring. An oil separates, which crystallizes; the desired 3-methoxy-phenyl benzoate is filtered off and recrystallized from ethanol, M.P. -87"; yield: 86.0 g.

A mixture, prepared from 86.0 g. of 3-methoxy-phenyl benzoate, 1,000 ml. of diethyl ether, 112.0 g. of potassium cyanide and 500 ml. of water, is stirred while adding 200 ml. of 30 percent sulfuric acid; approximately 2 ml. of the acid is added every thirty minutes for three hours, then dropwise. After stirring for five hours, the organic layer is separated and the aqueous phase is washed with diethyl ether; the combined organic extracts are washed with water, dried and evaporated. The desired Z-hydroxy- 2-.phenyl-3-(3-methoxy-phenyl)-oxy-propionitrile crystallizes on standing under reduced pressure, M.P. 86-87"; yield: 93.0 g.

To a solution of 23.0 g. of 2-hydroxy-2-phenyl-343- methoxy-phenyl)-oxy-propionitrile in 400 ml. of diethyl ether is added 12.0 g. of powdered anhydrous zinc chloride, and anhydrous hydrozen chloride is bubbled through the reaction mixture for two hours. After standing in the refrigerator for three days, it is treated with ice and water and is then heated on the steam bath. The solid material is filtered off and crystallized from ethyl acetate to yield 3-hydroxy-7-methoxy-3-phenyl-chroman 4 one, which .melts at 133-435"; yield: 8.3 g.

A mixture of 8.3 g. of 3-hydroxy-7-methoxy-3-phenylchroman-4-one, 25 ml. of pyridine and 25 ml. of acetic anhydride is heated at -115 for three hours, and is 3-acety1oxy-7-methoxy-3-phenyl-chrornan 4 one, which melts at 104-106".

A solution of 8.7 g. of 3-acetyloxy-7-methoxy-3- phenyl-chroman-4-one in 200 ml. of 70 percent aqueous acetic acid is heated to 100, and treated with 13.1 g. of zinc dust, which is added over a period of five minutes while stirring. After maintaining the reaction mixture at 100 for fifty minutes, it is filtered and diluted with Water. The organic precipitate is filtered off and crystallized from ethanol to yield 5.3 g. of 7-methoxy-3-phenyl-chroman-4- one, M.P. 78-85.

Example 2 The 4-[4-(2-N,N-diethylaminoethyl) oxy-phenyl1-7- methoxy-3-phenyl-2H-chromene hydrochloride, when dissolved in water and basified with sodium hydroxide, yields the 4-[4-(2 N,N-diethylaminoethyl)-oxy-phenyl]-7-methoxy-3-phenyl-2H-chromene, which is isolated by extracting it with diethyl ether, and evaporating the solvent; it is purified by distillation, RR 175 /0.55 mm.

Example 3 Upon treating the Grignard reagent prepared from 5.44 g. of 4-(2-N,N-diethylaminoethyl) -oxy-bromobenzene and 0.49 g. of magnesium according to the procedure described in Example 1, with a solution of 4.5 g. of 3-phenylchroman-4-one in 50 m1. of tetrahydrofuran, and working up the reaction mixture as described in Example 1, the 4-[4-(2-N,N-diethylaminoethyl)-oxy-phenyl] 3 phenyl- ZH-chromene of the formula is obtained and characterized in the form of its hydrochloride, or its picrate.

Example 4 Other compounds, which are prepared according to the above procedure by selecting the appropriate starting materials are, for example,

3 [4 (2 N,N diethylaminoethyl) oxy phenyl]- 6 methoxy 2 phenylbenzofuran, prepared by reacting 6 methoxy 2 phenyl 2,3 dihydrobenzofuran 3- one with the Grignard reagent from 4-(2-N,N-diethylaminoethyl)-oxy-bromobenzene and magnesium;

6 methoxy 2 phenyl 3 {4 [2 (1 pyrrolidino)- ethyl] oxy-pheny1}- benzofuran, prepared by reacting 6 methoxy 2 phenyl 2,3 dihydrobenzofuran 3- one with the Grignard reagent from 4-[2-( l-pyrrolidino)- ethy1]-oxy-bromobenzene and magnesium;

3 phenyl 4 {4 [2 (1 pyrrolidino) ethyl] oxyphenyl} 2H chromene, prepared by reacting 3 phenylchroman4-one with the Grignard reagent from 4-[2-(1- pyrrolidino)-ethyl]-oxy-bromobenzene and magnesium;

3 (4 methyl phenyl) 4 {4 [2 (1 piperidino)- ethyl]-oxy-phenyl}-2H-chromene, prepared by reacting 3-(4-methyl-phenyl)-chroman-4-one with the Grignard reagent from 4- [2-( l-piperidino)-ethy1]-oxy-bromobenzene and magnesium;

3 (4 methoxy phenyl) 4 [4 (2 N,N dimethylaminoethyl)-oxy-phenyl]-2H-chromene, prepared by reacting 3 (4-methoxy-phenyl) chroman-4-one with the Grignard reagent from 4-(2-N,N-dimethylaminoethyl)- oxy-bromobenzene and magnesium;

3 (4 chloro phenyl) 4 [4 (2 N,N diethyl- 16 aminoethyD-oxy-phenyl]-2H-chromene, prepared by reacting 3-(4-chloro-phenyl)-chroman-4-one with the Grignard reagent from 4 (2 N,N diethylaminoethyl) oxybromobcnzene and magnesium;

3 (4 chloro phenyl) 4 {4 [2 (1 pyrrolidino)- ethyl]-oxy-phenyl}-2H-chromene, prepared by reacting 3-(4-chloro-phenyl)-chrornan-4-one with the Grignard reagent from 4-[2-( l-pyrrolidino) -ethyl] -oxy-bromobenzene and magnesium;

3 (4 chloro phenyl) 4 [2,3,4 tri (2 N,N- diethylaminoethyl) oxy-phenyH-ZH-chromene, prepared by reacting 3-(4-chloro-phenyl)-chroman-4-one with the Grignard reagent from 2,3,4-trimethoxybromobenzene, treating the resulting 3-(4-chloro-phenyl)-4-(2,3,4-trimethoxy-phenyl)-2H-chromene with pyridine hydrochloride and reacting the sodium salt of 3-(4-chloro-phenyl)-4- (2,3,4-trihydroxy-phenyl) -2H-chrornene with 2-N,N-diethylaminoethyl chloride;

4 {4 [2 (4 morpholino) ethyl] oxy phenyl}- 3-phenyl-2H-chromene, prepared by reacting 3-phenylchroman-4-one with the Grignard reagent from 4-[2-(4- morpholino)-ethyl]-oxy-bromobenzene and magnesium;

7 chloro 4 [3 chloro 4 (2 N,N diethylaminoethyl)-oxy-phenyl]-3-phenyl-2H-chromene, prepared by reacting 7-chloro-3-phenyl-chroman-4-one with the Grignard reagent from 4-bromo-2-chloro-anisole and magnesium, hydrolizing the resulting 7-chloro-4-(4-methoxy-3- chloro-phenyl)-3-phenyl-2H-chromene with pyridine hydrochloride to form the 7-chloro-4-(3-chloro-4-hydroxyphenyl)-3-phenyl-2H-chromene, the sodium salt of which is then reacted with 2-N,N-diethylaminoethyl chloride;

5,7 dimethoxy 4 {4 [2 (4 methyl 1 piperazino) ethyl] oxy phenyl} 3 phenyl 2H chromene, prepared by reacting 5,7-dimethoxy-3-phenyl-chroman-4- one with the Grignard reagent from 4-[2-(4-methyl-lpiperazino -ethyl] -oxy-bromobenzene and magnesium;

4 [4 (3 N,N dimethylaminopropyl) oxy phenyl] 7 methyl 3 (3 pyridyl) 2H chromene, prepared by reacting 7-methyl-3-(3-pyridyl)-chrornan-4-one with the Grignard reagent from 4-(3-N,N-dimethylaminopropyl)-oxy-bromobenzene and magnesium;

3 [4 (2 N,N diethylaminoethyl) oxy phenyl]- 4-pheny1-2H-chromene, prepared by reacting. 3-(4-methoxy-phenyl)-chroman-4-one with the Grignard reagent from bromobenzene and magnesium, hydrolyzing the resulting 3 (4-methoxy-pheny1) 4-phenyl-2H-chromene with pyridine hydrochloride, and treating the sodium salt of 3 (4-hydroxy-pheny1) -4-phenyl-2H-chromene with 2-N,N-diethylaminoethyl chloride;

7 methoxy 3 phenyl 4 {4 [2 (1 pyrrolidino)- ethyl]-oxy-phenyl}-2H-chromene, prepared by reacting 7-methoxy-3-phenyl-chroman-4-one with the Grignard reagent from 4-[2-(1-pyrro1idino)-ethyl]-oxy-bromobenzene and magnesium;

5 [4 (2 N,N diethylaminoethyl) oxy phenyl]- 4-phenyl-2,3-dihydro-l-benzoxezipin, prepared by reacting 4 phenyl 2,3,4,5 tetrahydro l benzoxepin 5 one with the Grignard reagent from 4-(2-N,N-diethylaminoethyl)-oxy-bromobenzene and magnesium; and the like.

What is claimed is:

1. A member selected from the group consisting of a compound of the formula in Which Ph is a member selected from the group consisting of ortho-phenylene and ortho-phenylene substituted by one to four members selected from the group consistin g of lower alkyl, lower alkoxy, lower alke'nyloxy, lower alkylenedioxy, halogen, nitro, amino, di-lower a'lkylamino, trilluoromethyl, lower alkanoyl, benzoyl and pyridoyl, one

r 17 of the substituents Ru and R stands for the radical of the formula i Am-alk- O and the other stands for the radical of the formula RsRv R1 which separates the oxygen from the carbon atom of the double bond to which it is attached by at most vtwo carbon atoms, the-letter n is an integer from to 2, an acid addition salt thereof, an N-oxide thereof, an acid addition salt of an N-oxide thereof and 'a quaternary ammonium compound thereof.

2. A compound of the formula Ra Rb in which lPh' is a member selected from the group consisting of 1,2-phenylene, (lower alkyl) 1,2 phenylene, (lower alkoxy)-l,2-phenylene, and (halogeno)-1,2-phenylene, R is a member selected from the group consisting of phenyl, (lower alkyl)-phenyl, lower alkoXy)-,phenyl and (halogeno)-phenyl, the letter n is an integer'from 0 to 2, Am is a member selected from the group consisting of N,N-di-lower alkyl-amino, N,N-alkylene-imino, in which alkylene has from four to seven carbon atoms, 4-morpholinoand 4-lower alkyl-l-piperazino, the group of the formula --(C 'H stands for alkylene having from two to three carbon atoms and separates the group Am from the oxygen atom by two to three carbon atoms, and each of the groups R and R is a member selected from the group consisting of hydrogen, halogeno and the group of the formula -O(C 'H )Am' in which Am and the group of the formula --(C 'H have the previously-given meaning.

3. An acid addition salt of a compound of the formula in which Ph' is a member selected from the group consisting of 1,2-phenylene, ,(lower alkyl)-1,2-phenylene, (lower alkoxy)-l,2-phenylene, and (ha1ogeno)-1,2-phenylene, R is a member selected from the group consisting of phenyl, (lower alkyl)-phenyl, (lower a1koxy)-'phenyl and (halogeno)-phenyl, the letter n is an integer from 0 to 2, Am is a member selected from the group consisting of N,N-di-lower alkyl-amino, N,N-alkylene-imino, in which alkylene has from four to seven carbon atoms, 4- morpholino and 4-lower alkyl-l-piperazino, the group of the formula -(C 'H stands for alkylene having from two to three carbon atoms and separates the group Am from the oxygen atomby two to three carbon atoms, and each of the groups Rg-and R is a member selected from the group consisting (if hydrogen, ha'logeno arid the group of the formula -O- -(C H- ')--Am', in which Am and the group of the formula (C H have the previously-given meaning.

4. A compound of the formula 0 \CH2 Ra Ra 2Q Rs Rs in which Am" is a member selected from the group consisting of N,N-di-lower =alkyl-amino and N,N-alkyleneimino, in which alkylene has from four to seven carbon atoms, each of the groups R, and R is a member selected from the group consisting of hydrogen and the group of the formula O--CH CH -Am, in whichlAm" has the previously given meaning, and each of the groups R R, and R, is a member selected from the group consisting of hydrogen, lower alkyl, lower alkoxy and halogeno.

5. An acid addition salt of a compound of the formula Ra Rb in which Am" is a member selected from the group consisting of N,N-di-lower alkyl-amino and N,N-alkyleneimino, in which alkylene has from four to seven carbon atoms, each of the groups R,,' and R is a member selected from the group consisting of hydrogen and the group of the formula O-CH --CH -Am", in which Am" has the previously given meaning, and each of the groups R R and R is a member selected from the group consisting of hydrogen, lower a-lkyl, lower alkoxy and halogene.

6. 4-[4-(2-N,Ndiethylaminoethyl)-oxy phenyl] 3- phenyl-ZH-chromene.

7. An acid addition salt of 4-[4-(2-N,N-diethylaminoethyl) -oxy-phenyl] -3-phenyl-2H-chromene.

8. 4-[4-(2-N,N-diethylaminoethyl)-oxy phenyl] 7- methoxy-3-phenyl-2H-chromene.

9. An acid addition salt of 4-[4-(2-N,N-die'thylaminoethyl)-oxy-phenyl]-7-methoxy-3-phenyl-2H-chromene.

(References on following page) 19 20 References Cited Maitte, Chemical-Abstracts, vol. 49, columns 6929- m 6931 (1955). UNITED STAlES PATENTS. Allen et a1., Chemical Abstracts, vol. 46, column 3,142,682 I 7/1964 De Stevens 260+34S.2'X 5 1536) (1952)' OTHER REFERENCES I NORMA S. MILESTONE, Actzng Przmary Examiner. i WALTER A. MODANCE, Examiner. Lowenbemet a1., Chcmlcai Abstracts, vol. 19, pp. 286- J M. FORD, Assistant Examiner- UNITED STATES. PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,374,245 March 19, 1968 Richard William James Carney et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below: Column 17, llnes 35 to 45, the top portion of the formula should appear as shown below:

Signed and sealed this 27th day of January 1970: (SEAL) Attest- (1 1M151 M. Fletcher, Jr. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

